Effects of antibody induction on transplant outcomes in human leukocyte antigen zero-mismatch deceased donor kidney recipients.
We aimed to investigate the impact of antibody induction on outcomes in human leukocyte antigen (HLA) 0-mismatched deceased donor kidney recipients. Using the Organ Procurement and Transplant Network/United Network of Organ Sharing database as of November 2009, we identified 44,008 adult deceased donor kidney recipients who received primary kidney transplants alone between 2003 and 2008 (HLA 0 mismatch, n = 6274; ≥ 1 mismatch, n=37,734; median follow-up: 834 days). The impact of induction (thymoglobulin, interleukin-2 receptor antagonists [IL-2RA], or alemtuzumab; vs. no induction) on rejection (initial hospitalization, 6 months, first year), death-censored graft failure, and mortality were analyzed using multivariate logistic and Cox regression in the two groups. The impact of individual agents on outcomes was further analyzed in 0-mismatch recipients. There was a decreased risk of rejection over the first 6 months for HLA 0-mismatch recipients of antibody induction (adjusted odds ratio=0.71, P=0.003), but this effect was not observed at 1 year; in comparison, induction was associated with a reduced risk of rejection over the first year for HLA-mismatched recipients (0.87, P<0.001). The use of thymoglobulin (0.72, P=0.02) and IL-2RA (0.67, P=0.004) was associated with a decreased risk of rejection compared with no-induction at 6 months but was not different at 1 year (thymoglobulin: 0.77, P=0.05; IL-2RA:0.81, P=0.11) in HLA 0-mismatched recipients. Induction was not associated with improved graft or patient survival in HLA 0-mismatch recipients. In HLA 0-mismatch deceased donor recipients, antibody induction was associated with a decreased risk of rejection at 6 months posttransplant. Its use did not improve graft and patient survival over the follow-up period.


Local surface potential of π-conjugated nanostructures by Kelvin probe force microscopy: effect of the sampling depth.
Kelvin probe force microscopy (KPFM) is usually applied to map the local surface potential of nanostructured materials at surfaces and interfaces. KPFM is commonly defined as a 'surface technique', even if this assumption is not fully justified. However, a quantification of the surface sensitivity of this technique is crucial to explore electrical properties at the nanoscale. Here a versatile 3D model is presented which provides a quantitative explanation of KPFM results, taking into account the vertical structure of the sample. The model is tested on nanostructured films obtained from two relevant semiconducting systems for field-effect transistor and solar cell applications showing different interfacial properties, i.e., poly(3-hexylthiophene) (P3HT) and perylene-bis-dicarboximide (PDI). These findings are especially important since they enable quantitative determination of the local surface potential of conjugated nanostructures, and thereby pave the way towards optimization of the electronic properties of nanoscale architectures for organic electronic applications.


Cell Adhesion Induced Using Surface Modification with Cell-Penetrating Peptide-Conjugated Poly(ethylene glycol)-Lipid: A New Cell Glue for 3D Cell-Based Structures.
We synthesized a novel material, cell-penetrating peptide-conjugated poly(ethylene glycol)-lipid (CPP-PEG-lipid), that can induce the adhesion of floating cells. Firm cell adhesion with spreading could be induced by cell surface modification with the CPP-PEG-lipids. Cell adhesion was induced by CPPs but not by any other cationic short peptides we tested. Here, we demonstrated adherence using the floating cell line CCRF-CEM as well as primary human T cells, B cells, erythrocytes, and hepatocytes. As compared to cells grown in suspension, adherent cells were more rapidly induced to attach to substrates with the cell-surface modification. The critical factor for attachment was localization of CPPs at the cell membrane by PEG-lipids with PEG > 20 kDa. These cationic CPPs on PEG chains were able to interact with substrate surfaces such as polystyrene (PS) surfaces, glass surfaces, and PS microfibers that are negatively charged, inducing firm cell adhesion and cell spreading. Also, as opposed to normal cationic peptides that interact strongly with cell membranes, CPPs were less interactive with the cell surfaces because of their cell-penetrating property, making them more available for adhering cells to the substrate surface. No effects on cell viability or cell proliferation were observed after the induction of cell adhesion. With this technique, cells could be easily immobilized onto PS microfibers, an important step in fabricating 3D cell-based structures. Cells immobilized onto 3D PS microfibers were alive, and human hepatocytes showed normal production of urea and albumin on the microfibers. This method is novel in inducing firm cell adhesion via a one-step treatment.


Eating habits modulate short term memory and epigenetical regulation of brain derived neurotrophic factor in hippocampus of low- and high running capacity rats.
Exercise capacity and dietary restriction (DR) are linked to improved quality of life, including enhanced brain function and neuro-protection. Brain derived neurotrophic factor (BDNF) is one of the key proteins involved in the beneficial effects of exercise on brain. Low capacity runner (LCR) and high capacity runner (HCR) rats were subjected to DR in order to investigate the regulation of BDNF. HCR-DR rats out-performed other groups in a passive avoidance test. BDNF content increased significantly in the hippocampus of HCR-DR groups compared to control groups (p<0.05). The acetylation of H3 increased significantly only in the LCR-DR group. However, chip-assay revealed that the specific binding between acetylated histone H3 and BNDF promoter was increased in both LCR-DR and HCR-DR groups. In spite of these increases in binding, at the transcriptional level only, the LCR-DR group showed an increase in BDNF mRNA content. Additionally, DR also induced the activity of cAMP response element-binding protein (CREB), while the content of SIRT1 was not altered. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) was elevated in HCR-DR groups. But, based on the levels of nuclear respiratory factor-1 and cytocrome c oxidase, it appears that DR did not cause mitochondrial biogenesis. The data suggest that DR-mediated induction of BDNF levels includes chromatin remodeling. Moreover, DR does not induce mitochondrial biogenesis in the hippocampus of LCR/HCR rats. DR results in different responses to a passive avoidance test, and BDNF regulation in LCR and HCR rats.


Surgical management of first caudal nerve root foraminal compression secondary to intervertebral disc disease in a Cocker Spaniel.
A nine-year-old spayed female Cocker Spaniel was investigated for an eight week history of licking and rubbing at the tail base, dullness, and signs of pain on manipulation of the tail. Left-sided intraforaminal compression of the first caudal nerve root due to intervertebral disc disease was diagnosed by radiographic, computed tomography, and magnetic resonance imaging examinations. The dog was nonresponsive to conservative medical therapy. A decompressive left-sided first-second caudal (Cd1-Cd2) foraminotomy was performed. Postoperative computed tomography confirmed surgical decompression of the involved nerve root. At the one month follow-up examination there was marked improvement in clinical signs. At two months, clinical signs were completely resolved and there was not any evidence of recurrence twelve months after surgery. Intervertebral disc disease should be considered as a differential diagnosis in dogs with discomfort at the tail base or signs of pain on manipulation of the tail. Surgical decompression may be indicated for management of these cases. This is the first report of diagnosis and surgical management of caudal intervertebral disc disease by foraminotomy in the dog. Surgical decompression by foraminotomy may therefore be a treatment option for this condition.


The psychological and physiological effects of acute occupational stress in new anesthesiology residents: a pilot trial.
Occupational stress in resident physicians has profound implications for wellness, professionalism, and patient care. This observational pilot trial measured psychological and physiological stress biomarkers before, during, and after the start of anesthesia residency. Eighteen physician interns scheduled to begin anesthesia residency were recruited for evaluation at three time points: baseline (collected remotely before residency in June 2013); first-month visit 1 (July); and follow-up visit 2 (residency months 3 to 5, September-November). Validated scales were used to measure stress, anxiety, resilience, and wellness at all three time points. During visits 1 and 2, the authors measured resting heart-rate variability, responses to laboratory mental stress (hemodynamic, catecholamine, cortisol, and interleukin-6), and chronic stress indices (C-reactive protein, 24-h ambulatory heart rate and blood pressure, 24-h urinary cortisol and catecholamines, overnight heart-rate variability). Thirteen interns agreed to participate (72% enrollment). There were seven men and six women, aged 27 to 33 yr. The mean ± SD of all study variables are reported. The novelty of this report is the prospective design in a defined cohort of residents newly exposed to the similar occupational stress of the operating environment. Because of the paucity of literature specific to the measures and stress conditions in this investigation, no data were available to generate a priori definition of primary outcomes and a data analytic plan. These findings will allow power analysis for future design of trials examining occupational stress and stress-reducing interventions. Given the importance of physician burnout in our country, the impact of chronic stress on resident wellness requires further study.


Variation in the recall of socially rewarding information and depressive symptom severity: a prospective cohort study.
To test the association between recall for socially rewarding (positive) and/or socially critical (negative) information and depressive symptoms. Cohort study of people who had visited UK primary care in the past year reporting depressive symptoms (N = 558, 69% female). Positive and negative recall was assessed at three time-points, 2 weeks apart, using a computerised task. Depressive symptoms were assessed at four time-points using the Beck Depression Inventory (BDI). Analyses were conducted using multilevel models. Concurrently we found evidence that, for every increase in two positive words recalled, depressive symptoms reduced by 0.6 (95% CI -1.0 to -0.2) BDI points. This association was not affected by adjustment for confounders. There was no evidence of an association between negative recall and depressive symptoms (-0.1, 95% CI -0.5 to 0.3). Longitudinally, we found more evidence that positive recall was associated with reduced depressive symptoms than vice versa. People with more severe depressive symptoms recall less positive information, even if their recall of negative information is unaltered. Clinicians could put more emphasis on encouraging patients to recall positive, socially rewarding information, rather than trying to change negative interpretations of events that have already occurred.


In-parallel artificial lung attachment at high flows in normal and pulmonary hypertension models.
End-stage lung disease patients who require a thoracic artificial lung (TAL) must be extubated and rehabilitated prior to lung transplantation. The purpose of this study is to evaluate hemodynamics and TAL function under simulated rest and exercise conditions in normal and pulmonary hypertension sheep models. The TAL, the MC3 Biolung (MC3, Inc, Ann Arbor, MI), was attached between the pulmonary artery and left atrium in nine normal sheep and eight sheep with chronic pulmonary hypertension. An adjustable band was placed around the distal pulmonary artery to control the percentage of cardiac output (CO) diverted to the TAL. Pulmonary system hemodynamics and TAL function were assessed at baseline (no flow to the TAL) and with approximately 60%, 75%, and 90% of CO diverted to the TAL. Intravenous dobutamine (0, 2, and 5 mcg . kg(-1). min(-1)) was used to simulate rest and exercise conditions. At 0 and 2 mcg . kg(-1). min(-1), CO did not change significantly with flow diversion to the TAL for both models. At 5 mcg . kg(-1). min(-1), CO decreased with increasing TAL flow up to 28% +/- 5% in normal sheep and 23% +/- 5% in pulmonary hypertension sheep at 90% flow diversion to the artificial lung. In normal sheep, the pulmonary system zeroth harmonic impedance modulus, Z(0), increased with increasing flow diversion. In hypertensive sheep, Z(0) decreased at 60% and 75% flow diversion and returned to baseline levels at 90%. The TAL outlet blood oxygen saturation was 95% or greater under all conditions. Pulmonary artery to left atrial TAL use will not decrease CO during rest or mild exercise but may not allow more vigorous exercise.


Preprocedural Checklist for Magnetic Resonance Imaging Patients Undergoing General Anesthesia: A Process Improvement Plan to Enhance Reimbursement.
Thorough documentation is essential for hospital reimbursement from payors such as the Centers for Medicare & Medicaid Services. Inconsistencies and incomplete documentation can occur if workflow is not standardized especially in cases with interdisciplinary involvement. Documentation for patients undergoing magnetic resonance imaging (MRI) with anesthesia services was examined and revealed an opportunity for improvement to avoid financial losses. A preprocedure checklist to improve documentation and standardize workflow was implemented. We compared documentation from preintervention MRI to postintervention MRI with anesthesia services. Documentation that met the reimbursement requirements increased from 5% in the preintervention group to 90% in the postintervention group after the preprocedural checklist implementation. A cost estimate showed a reduction in potential revenue loss from preimplementation to postimplementation groups. The standardization of workflow with the aid of checklists helped meet the documentation requirements for adequate reimbursements and reduced the risk of potential reimbursement losses from payors.


Polyferrocenylsilanes: synthesis, properties, and applications.
This in-depth review covers progress in the area of polyferrocenylsilanes (PFS), a well-established, readily accessible class of main chain organosilicon metallopolymer consisting of alternating ferrocene and organosilane units. Soluble, high molar mass samples of these materials were first prepared in the early 1990s by ring-opening polymerisation (ROP) of silicon-bridged [1]ferrocenophanes (sila[1]ferrocenophanes). Thermal, transition metal-catalysed, and also two different living anionic ROP methodologies have been developed: the latter permit access to controlled polymer architectures, such as monodisperse PFS homopolymers and block copolymers. Depending on the substituents, PFS homopolymers can be amorphous or crystalline, and soluble in organic solvents or aqueous media. PFS materials have attracted widespread attention as high refractive index materials, electroactuated redox-active gels, fibres, films, and nanoporous membranes, as precursors to nanostructured magnetic ceramics, and as etch resists to plasmas and other radiation. PFS block copolymers form phase-separated iron-rich, redox-active and preceramic nanodomains in the solid state with applications in nanolithography, nanotemplating, and nanocatalysis. In selective solvents functional micelles with core-shell structures are formed. Block copolymers with a crystallisable PFS core-forming block were the first to be found to undergo "living crystallisation-driven self-assembly" in solution, a controlled method of assembling block copolymers into 1D or 2D structures that resembles a living covalent polymerisation, but on a longer length scale of 10 nm-10 μm.


Local sensitivity to stimulus orientation and spatial frequency within the receptive fields of neurons in visual area 2 of macaque monkeys.
We used dynamic dense noise stimuli and local spectral reverse correlation methods to reveal the local sensitivities of neurons in visual area 2 (V2) of macaque monkeys to orientation and spatial frequency within their receptive fields. This minimized the potentially confounding assumptions that are inherent in stimulus selections. The majority of neurons exhibited a relatively high degree of homogeneity for the preferred orientations and spatial frequencies in the spatial matrix of facilitatory subfields. However, about 20% of all neurons showed maximum orientation differences between neighboring subfields that were greater than 25 deg. The neurons preferring horizontal or vertical orientations showed less inhomogeneity in space than the neurons preferring oblique orientations. Over 50% of all units also exhibited suppressive profiles, and those were more heterogeneous than facilitatory profiles. The preferred orientation and spatial frequency of suppressive profiles differed substantially from those of facilitatory profiles, and the neurons with suppressive subfields had greater orientation selectivity than those without suppressive subfields. The peak suppression occurred with longer delays than the peak facilitation. These results suggest that the receptive field profiles of the majority of V2 neurons reflect the orderly convergence of V1 inputs over space, but that a subset of V2 neurons exhibit more complex response profiles having both suppressive and facilitatory subfields. These V2 neurons with heterogeneous subfield profiles could play an important role in the initial processing of complex stimulus features.


A common neural substrate for language production and verbal working memory.
Verbal working memory (VWM), the ability to maintain and manipulate representations of speech sounds over short periods, is held by some influential models to be independent from the systems responsible for language production and comprehension [e.g., Baddeley, A. D. Working memory, thought, and action. New York, NY: Oxford University Press, 2007]. We explore the alternative hypothesis that maintenance in VWM is subserved by temporary activation of the language production system [Acheson, D. J., & MacDonald, M. C. Verbal working memory and language production: Common approaches to the serial ordering of verbal information. Psychological Bulletin, 135, 50-68, 2009b]. Specifically, we hypothesized that for stimuli lacking a semantic representation (e.g., nonwords such as mun), maintenance in VWM can be achieved by cycling information back and forth between the stages of phonological encoding and articulatory planning. First, fMRI was used to identify regions associated with two different stages of language production planning: the posterior superior temporal gyrus (pSTG) for phonological encoding (critical for VWM of nonwords) and the middle temporal gyrus (MTG) for lexical-semantic retrieval (not critical for VWM of nonwords). Next, in the same subjects, these regions were targeted with repetitive transcranial magnetic stimulation (rTMS) during language production and VWM task performance. Results showed that rTMS to the pSTG, but not the MTG, increased error rates on paced reading (a language production task) and on delayed serial recall of nonwords (a test of VWM). Performance on a lexical-semantic retrieval task (picture naming), in contrast, was significantly sensitive to rTMS of the MTG. Because rTMS was guided by language production-related activity, these results provide the first causal evidence that maintenance in VWM directly depends on the long-term representations and processes used in speech production.


Oncogenic transformation and hypoxia synergistically act to modulate vascular endothelial growth factor expression.
Hypoxia can select for cells that have lost their apoptotic potential, thereby making them resistant to adverse conditions. However, long-term survival of transformed cells which have diminished apoptotic sensitivity when exposed to low oxygen conditions would require the activation of their angiogenic program to compensate for an insufficient oxygen supply. In this report, we show that the activity (of oncogenic Ha-ras, either constitutively or transiently, enhances the induction of the angiogenic mitogen, vascular endothelial growth factor (VEGF), by hypoxia. Analysis of the 5' flanking region of the VEGF promoter indicates that a HIF-1-like sequence is to promote a 15-fold increase in reporter gene activity in Ha-ras-transformed cells when exposed to hypoxia, whereas mutations in the same site totally inhibited VEGF induction. Under low oxygen conditions, VEGF induction is inhibited in cells expressing a mutant inhibitory allele of Ha-ras (RasN17), indicating a direct role for Ras in modulating VEGF activity. We propose that the angiogenic switch in Ras-transformed cells may be physiologically promoted by the tumor microenvironment through VEGF induction.


Perceptions of adult trauma patients on the acceptability of text messaging as an aid to reduce harmful drinking behaviours.
Brief interventions (BIs) have been shown to be effective in modifying hazardous drinking behaviours in a range of settings. However, they are underutilised in hospitals due to resource constraints. We explored the perspectives of admitted trauma patients about the appeal, acceptability and content of a Brief Intervention (BI) delivered via text messages. Thirty mobile phone users (≥16 years old) admitted to Auckland City Hospital as a result of injury were recruited (December 2010 - January 2011). Participants were interviewed face-to-face during their hospital stay using a semi-structured interview guide that explored topics including perceptions of the proposed intervention to reduce hazardous drinking and related harm, and perceived acceptability of an m-health program. Where issues relating to content of messages were raised by participants these were also captured. In addition, a brief survey captured information on demographic information, mobile phone usage and type of phone, along with the frequency of alcohol use. 22 of the 30 participants were male, and almost half were aged 20 to 39 years. The majority of participants identified as New Zealand Europeans, six as Māori (New Zealand's indigenous population) and of the remainder two each identified as Pacific and of Asian ethnicity. Most (28/30) participants used a mobile phone daily. 18 participants were deemed to be drinking in a non-hazardous manner, seven were hazardous drinkers, and three were non-drinkers. Most participants (21/30) indicated that text messages could be effective in reducing hazardous drinking and related harms, with more than half (17/30) signalling they would sign-up. Factors identified that would increase receptiveness included: awareness that the intervention was evidence-based; participants readiness-to-change; informative messages that include the consequences of drinking and practical advice; non-judgemental messages; and ease-of-use. Areas of potential concern included: confidentiality and frequency of messages. The cultural relevance of the messages for Māori was highlighted as important. This study indicates that trauma patients recognize potential benefits of mobile-health interventions designed to reduce hazardous drinking. The feedback provided will inform the development of an intervention to be evaluated in a randomised controlled trial.


Trying to restore justice: bureaucracies, risk management, and disciplinary boundaries in New Zealand criminal justice.
New Zealand is well known for its restorative justice conferences in the youth justice system. However, restorative justice has yet to overwhelm the adult criminal justice system. Based on interviews in New Zealand with correctional staff, restorative justice providers, and others, this article explores the reason for the modest inroads that restorative practice has made, and suggests that the general context may explain the limits of restorative justice in other places. The article argues that bureaucratic silos make it challenging to determine if restorative practice might fit within a rehabilitation or reintegration framework. In addition, because of the dominance of psychological modes for assessing and treating criminal behavior, an overarching preoccupation with risk management orients correctional practice toward treatment. Moreover, restorative justice's affiliation with victims' perspectives has made its placement within offender reintegration difficult to imagine. Finally, the penal populism that frames correctional practice in New Zealand, and other Anglophone countries, makes alternative to punishment harder to sell. However, the current liminal state of correctional practice creates an opportunity to conceive of more humanistic ways of repairing the harm caused by crime.


Morbidity and mortality associated with spinal surgery in children: a review of the Scoliosis Research Society morbidity and mortality database.
Currently, few studies regarding morbidity and mortality associated with operative treatment of spinal disorders in children are available to guide the surgeon. This study provides more detailed morbidity and mortality data with an analysis of 23,918 pediatric cases reported in the multicenter, multisurgeon Scoliosis Research Society morbidity and mortality database. The Scoliosis Research Society morbidity and mortality database was queried for the years from 2004 to 2007. The inclusion criterion was age 18 years or younger. Cases were categorized by operation type and diagnosis. Details on the surgical approach, use of neurophysiological monitoring, and type of instrumentation were recorded. Major perioperative complications and deaths were evaluated. Statistical analysis was performed with chi-square testing, with a p value < 0.05 considered significant. A total of 23,918 patients were included. The mean age was 13 ± 3.6 years (± SD). Spinal pathology included the following: scoliosis (in 19,642 patients), kyphosis (in 1455), spondylolisthesis (in 748), trauma (in 478), and other (in 1595 patients). The overall complication rate was 8.5%. Major complications included wound infections (2.7%), new neurological deficits (1.4%), implant-related complications (1.6%), and hematomas (0.4%). The most common medical complications were respiratory related (0.9%). Morbidity rates differed based on pathology, with patients undergoing treatment for kyphosis and spondylolisthesis having higher overall rates of morbidity (14.7% and 9.6%, respectively). Patients undergoing revision procedures (2034) or corrective osteotomies (2787) were more likely to suffer a complication or new neurological deficit. The majority of these deficits improved at least partially. Thirty-one deaths were reported for an overall rate of 1.3 per 1000. Respiratory complications were the most common cause of mortality (13 cases). Twenty-six of the deaths occurred in children undergoing scoliosis correction. Spinal surgery in children is associated with a range of complications depending on the type of operation. Mortality rates for all indications and operations were low. Patients undergoing more aggressive corrective procedures for deformity are more likely to suffer complications and new neurological deficits.


Mindfulness-based cognitive therapy as a treatment for chronic depression: A preliminary study.
This pilot study investigated the effectiveness of Mindfulness-Based Cognitive Therapy (MBCT), a treatment combining mindfulness meditation and interventions taken from cognitive therapy, in patients suffering from chronic-recurrent depression. Currently symptomatic patients with at least three previous episodes of depression and a history of suicidal ideation were randomly allocated to receive either MBCT delivered in addition to treatment-as-usual (TAU; N=14 completers) or TAU alone (N=14 completers). Depressive symptoms and diagnostic status were assessed before and after treatment phase. Self-reported symptoms of depression decreased from severe to mild levels in the MBCT group while there was no significant change in the TAU group. Similarly, numbers of patients meeting full criteria for depression decreased significantly more in the MBCT group than in the TAU group. Results are consistent with previous uncontrolled studies. Although based on a small sample and, therefore, limited in their generalizability, they provide further preliminary evidence that MBCT can be used to successfully reduce current symptoms in patients suffering from a protracted course of the disorder.


All-benzene carbon nanocages: size-selective synthesis, photophysical properties, and crystal structure.
The design and synthesis of a series of carbon nanocages consisting solely of benzene rings are described. Carbon nanocages are appealing molecules not only because they represent junction unit structures of branched carbon nanotubes, but also because of their potential utilities as unique optoelectronic π-conjugated materials and guest-encapsulating hosts. Three sizes of strained, conjugated [n.n.n]carbon nanocages (1, n = 4; 2, n = 5; 3, n = 6) were synthesized with perfect size-selectivity. Cyclohexane-containing units and 1,3,5-trisubstituted benzene-containing units were assembled to yield the minimally strained bicyclic precursors, which were successfully converted into the corresponding carbon nanocages via acid-mediated aromatization. X-ray crystallography of 1 confirmed the cage-shaped structure with an approximately spherical void inside the cage molecule. The present studies revealed the unique properties of carbon nanocages, including strain energies, size-dependent absorption and fluorescence, as well as unique size-dependency for the electronic features of 1-3.


Malignant Peripheral Nerve Sheath Tumors: From Epigenome to Bedside.
Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas typically developing in the context of neurofibromatosis type 1 (NF-1). With the exception of surgical resection, these tumors are resistant to all current therapies, and unresectable, recurrent, or metastatic tumors are considered incurable. Preclinical studies have identified several novel candidate molecular targets for therapeutic intervention, but, to date, targeted therapies have proven ineffective. Recent studies have identified recurrent mutations in polycomb repressive complex 2 (PRC2) core components, embryonic ectoderm development protein (EED) and suppressor of zeste 12 homolog (SUZ12), in MPNST. These mutations result in global loss of the histone H3 lysine 27 trimethylation epigenetic mark, normally deposited by PRC2, and subsequent gain in acetylation at this residue. This altered chromatin state has been shown to promote MPNST malignancy; however, acetylation at this residue sensitizes MPNSTs to BRD4 and bromodomain and extra-terminal domain inhibition. Interestingly, the catalytic component of PRC2, enhancer of zeste homolog 2 (EZH2), is not mutated in MPNST, hinting that a noncanonical, PRC2-independent function of EZH2 may play a role in this cancer. This review examines the pathobiology of MPNST, the contribution of PRC2 subunits to this process, and the prospects for PRC2-related therapies for this cancer. IMPLICATIONS: Identification of mutations in the PRC2 components EED and SUZ12 in the majority of MPNSTs may imply noncanonical oncogenic activities of the intact component, EZH2, and provide new opportunities for therapeutic intervention.


Use of Preventive Health Services in People With Serious Mental Illness: Consumer Perspectives on Barriers and Solutions.
This study asked 350 consumers with serious mental illness (DSM-IV) (who are using community mental health services in Sacramento County, California) for their perspective about barriers and solutions to use of preventive health services. Two questions were posed: (1) What do you think keeps you from getting preventive tests? (2) What do you think would help you complete the recommended tests? Participants were interviewed between October 2010 and December 2012. A mixed qualitative and quantitative data analysis method was used to examine participant responses. Perceived barriers included low priority (n = 64, 20%), doctor (did not order) (n = 55, 17%), finances/insurance barriers (n = 45, 14%), fear (n = 39, 12%), and knowledge about the services (n = 31, 10%). Common solutions included doctor-related interventions (n = 75, 23%), information (n = 61, 19%), insurance coverage (n = 49, 15%), transportation (n = 36, 11%), and use of reminders (n = 28, 9%). Consumers suggest that interventions may include providing more information and reminding doctors to order the tests and patients to complete the tests.


Integrating science into management of ecosystems in the Greater Blue Mountains.
Effective management of large protected conservation areas is challenged by political, institutional and environmental complexity and inconsistency. Knowledge generation and its uptake into management are crucial to address these challenges. We reflect on practice at the interface between science and management of the Greater Blue Mountains World Heritage Area (GBMWHA), which covers approximately 1 million hectares west of Sydney, Australia. Multiple government agencies and other stakeholders are involved in its management, and decision-making is confounded by numerous plans of management and competing values and goals, reflecting the different objectives and responsibilities of stakeholders. To highlight the complexities of the decision-making process for this large area, we draw on the outcomes of a recent collaborative research project and focus on fire regimes and wild-dog control as examples of how existing knowledge is integrated into management. The collaborative research project achieved the objectives of collating and synthesizing biological data for the region; however, transfer of the project's outcomes to management has proved problematic. Reasons attributed to this include lack of clearly defined management objectives to guide research directions and uptake, and scientific information not being made more understandable and accessible. A key role of a local bridging organisation (e.g., the Blue Mountains World Heritage Institute) in linking science and management is ensuring that research results with management significance can be effectively transmitted to agencies and that outcomes are explained for nonspecialists as well as more widely distributed. We conclude that improved links between science, policy, and management within an adaptive learning-by-doing framework for the GBMWHA would assist the usefulness and uptake of future research.


The Bigger They Are: Relationships between Body Height and Mass with the Body Drag Task in Law Enforcement Recruits.
California law enforcement recruits must perform a body drag before they graduate academy. While this task may be challenging for smaller recruits, no research has analyzed height and body mass relationships with the body drag. Data from 643 recruits (542 males, 101 females) who completed the drag in the final weeks of academy were analyzed. The recruits lifted a 74.84-kg, 1.73-m tall dummy and dragged it 9.75 m as quickly as possible. Independent samples t-tests compared the sexes; partial correlations controlling for sex detailed relationships between height and body mass with drag time. Recruits were split into quartile groups (based on sample size) for height and body mass (Group 1: shortest, lightest; Group 4: tallest, heaviest). A one-way MANOVA, with sex as a covariate, and Bonferroni post hoc, compared the groups. Male recruits were taller, heavier, and completed the drag faster than females (p < 0.001). There were small relationships between height (r = -0.255) and body mass (r = -0.211) with drag time. When split into height groups, the shortest recruits (Group 1) completed the drag 23-37% slower than all groups (p ≤ 0.031). When split into body mass groups, the lightest recruits (Group 1) were 23-35% slower than all groups (p ≤ 0.007). Most females (94-96%) were placed in Groups 1 or 2. Height and body mass could influence drag performance. Taller recruits may be able to lift the dummy off the ground, reducing friction, while heavier recruits may produce more force. Female and smaller male recruits should complete strength and power training to mitigate body size limitations.


A longitudinal analysis of maternal serum insulin-like growth factor I (IGF-I) and total and nonphosphorylated IGF-binding protein-1 in human pregnancies complicated by intrauterine growth restriction.
In cord blood and late gestation maternal serum, IGF-I is positively correlated with birth weight, whereas IGF-binding protein-1 (IGFBP-1) is inversely correlated with birth weight. Our goal was to determine whether maternal serum or amniotic fluid concentrations of IGF-I, IGFBP-1, or nonphosphorylated IGFBP-1 (npIGFBP-1) in early gestation predict later fetal growth abnormalities. Maternal serum was collected prospectively across gestation (5-40 wk) from 749 pregnant subjects. Amniotic fluid was collected after amniocentesis during wk 15-26 from 207 subjects. We compared median serum concentrations of IGF-I, IGFBP-1, and npIGFBP-1 in 38 subjects who delivered growth-restricted infants with the control group of 236 subjects with normal weight infants for each gestational age grouping, wk 5-12, 13-23, and 24-34. In the control group median IGF-I concentrations were 14.8, 11, and 15.6 nmol/liter for wk 5-12, 13-23, and 24-34, respectively, compared with 13.7, 14.3, and 10.6 nmol/liter in the intrauterine growth restriction (IUGR) group. Median IGFBP-1 concentrations were 8.5, 30.4, and 24.4 nmol/liter, respectively, in controls, compared with 11.4, 28.6, and 25.5 nmol/liter in the IUGR group. Median npIGFBP-1 concentrations were 6.9, 22, and 17.4 nmol/liter, respectively, in controls, compared with 5.0, 32.1, and 24.2 nmol/liter in the IUGR group. In the control group the median amniotic fluid IGFBP-1 level was 13,160 nmol/liter, and the median npIGFBP-1 level was 15,970 nmol/liter; in the IUGR group these levels were 13,440 and 18,440 nmol/liter, respectively. No clinically useful differences were found between the IUGR and control groups. Our results do not support the use of maternal serum IGF-I or IGFBP-1 or amniotic fluid IGFBP-1 or npIGFBP-1 early in gestation to predict later fetal growth restriction.


One-year delayed effect of fog on malaria transmission: a time-series analysis in the rain forest area of Mengla County, south-west China.
Malaria is a major public health burden in the tropics with the potential to significantly increase in response to climate change. Analyses of data from the recent past can elucidate how short-term variations in weather factors affect malaria transmission. This study explored the impact of climate variability on the transmission of malaria in the tropical rain forest area of Mengla County, south-west China. Ecological time-series analysis was performed on data collected between 1971 and 1999. Auto-regressive integrated moving average (ARIMA) models were used to evaluate the relationship between weather factors and malaria incidence. At the time scale of months, the predictors for malaria incidence included: minimum temperature, maximum temperature, and fog day frequency. The effect of minimum temperature on malaria incidence was greater in the cool months than in the hot months. The fog day frequency in October had a positive effect on malaria incidence in May of the following year. At the time scale of years, the annual fog day frequency was the only weather predictor of the annual incidence of malaria. Fog day frequency was for the first time found to be a predictor of malaria incidence in a rain forest area. The one-year delayed effect of fog on malaria transmission may involve providing water input and maintaining aquatic breeding sites for mosquitoes in vulnerable times when there is little rainfall in the 6-month dry seasons. These findings should be considered in the prediction of future patterns of malaria for similar tropical rain forest areas worldwide.


Quantitative analysis of virus and plasmid trafficking in cells.
Intracellular transport of DNA carriers is a fundamental step of gene delivery. By combining both theoretical and numerical approaches we study here single and several viruses and DNA particles trafficking in the cell cytoplasm to a small nuclear pore. We present a physical model to account for certain aspects of cellular organization, starting with the observation that a viral trajectory consists of epochs of pure diffusion and epochs of active transport along microtubules. We define a general degradation rate to describe the limitations of the delivery of plasmid or viral particles to a nuclear pore imposed by various types of direct and indirect hydrolysis activity inside the cytoplasm. By replacing the switching dynamics by a single steady state stochastic description, we obtain estimates for the probability and the mean time for the first one of many particles to go from the cell membrane to a small nuclear pore. Computational simulations confirm that our model can be used to analyze and interpret viral trajectories and estimate quantitatively the success of nuclear delivery.


Seasonal variation in host susceptibility and cycles of certain infectious diseases.
Seasonal cycles of infectious diseases have been variously attributed to changes in atmospheric conditions, the prevalence or virulence of the pathogen, or the behavior of the host. Some observations about seasonality are difficult to reconcile with these explanations. These include the simultaneous appearance of outbreaks across widespread geographic regions of the same latitude; the detection of pathogens in the off-season without epidemic spread; and the consistency of seasonal changes, despite wide variations in weather and human behavior. In contrast, an increase in susceptibility of the host population, perhaps linked to the annual light/dark cycle and mediated by the pattern of melatonin secretion, might account for many heretofore unexplained features of infectious disease seasonality. Ample evidence indicates that photoperiod-driven physiologic changes are typical in mammalian species, including some in humans. If such physiologic changes underlie human resistance to infectious diseases for large portions of the year and the changes can be identified and modified, the therapeutic and preventive implications may be considerable.


Impact of COVID-19 pandemic on mobility in ten countries and associated perceived risk for all transport modes.
The restrictive measures implemented in response to the COVID-19 pandemic have triggered sudden massive changes to travel behaviors of people all around the world. This study examines the individual mobility patterns for all transport modes (walk, bicycle, motorcycle, car driven alone, car driven in company, bus, subway, tram, train, airplane) before and during the restrictions adopted in ten countries on six continents: Australia, Brazil, China, Ghana, India, Iran, Italy, Norway, South Africa and the United States. This cross-country study also aims at understanding the predictors of protective behaviors related to the transport sector and COVID-19. Findings hinge upon an online survey conducted in May 2020 (N = 9,394). The empirical results quantify tremendous disruptions for both commuting and non-commuting travels, highlighting substantial reductions in the frequency of all types of trips and use of all modes. In terms of potential virus spread, airplanes and buses are perceived to be the riskiest transport modes, while avoidance of public transport is consistently found across the countries. According to the Protection Motivation Theory, the study sheds new light on the fact that two indicators, namely income inequality, expressed as Gini index, and the reported number of deaths due to COVID-19 per 100,000 inhabitants, aggravate respondents' perceptions. This research indicates that socio-economic inequality and morbidity are not only related to actual health risks, as well documented in the relevant literature, but also to the perceived risks. These findings document the global impact of the COVID-19 crisis as well as provide guidance for transportation practitioners in developing future strategies.


H2S and reactive sulfur signaling at the host-bacterial pathogen interface.
Bacterial pathogens that cause invasive disease in the vertebrate host must adapt to host efforts to cripple their viability. Major host insults are reactive oxygen and reactive nitrogen species as well as cellular stress induced by antibiotics. Hydrogen sulfide (H2S) is emerging as an important player in cytoprotection against these stressors, which may well be attributed to downstream more oxidized sulfur species termed reactive sulfur species (RSS). In this review, we summarize recent work that suggests that H2S/RSS impacts bacterial survival in infected cells and animals. We discuss the mechanisms of biogenesis and clearance of RSS in the context of a bacterial H2S/RSS homeostasis model and the bacterial transcriptional regulatory proteins that act as "sensors" of cellular RSS that maintain H2S/RSS homeostasis. In addition, we cover fluorescence imaging- and MS-based approaches used to detect and quantify RSS in bacterial cells. Last, we discuss proteome persulfidation (S-sulfuration) as a potential mediator of H2S/RSS signaling in bacteria in the context of the writer-reader-eraser paradigm, and progress toward ascribing regulatory significance to this widespread post-translational modification.


Bronchoalveolar lavage surfactant protein a, B, and d concentrations in preterm infants ventilated for respiratory distress syndrome receiving natural and synthetic surfactants.
Surfactant proteins (SPs) play an important role in surfactant metabolism and function. Understanding their relative contribution to clinical outcome remains incomplete. Exogenous surfactants differ in their SP content and physiologic effects. The aims of this study were to measure bronchoalveolar lavage (BAL) SP concentrations from preterm infants ventilated for respiratory distress syndrome and to assess their association with clinical outcome. Fifty preterm infants randomized to receive a natural or synthetic surfactant were lavaged each day for the first week and twice weekly thereafter using a standardized nonbronchoscopic technique. BAL SP-A, SP-B, and SP-D concentrations were measured using ELISA. Median BAL SP-A, SP-B, and SP-D concentrations for the whole cohort rose significantly during the first postnatal week (p < 0.05). SP-A concentration did not differ between outcome groups. BAL SP-B concentration rose significantly in lungs that were not supplemented with SP-B. Infants dying had significantly lower BAL SP-B concentrations on d 2 and 6 compared with survivors. BAL SP-D concentrations were significantly lower on d 2 and 3 among infants in supplemental oxygen on d 28 compared with those in air. BAL SP-A and SP-D concentrations did not differ significantly between infants randomized to receive a natural or synthetic surfactant. Lower BAL SP-B and SP-D but not SP-A concentrations were associated with worse clinical prognosis.


Factors influencing the shedding of verocytotoxin-producing Escherichia coli O157 by beef suckler cows.
A study was designed to investigate management factors that might influence the shedding of verocytotoxin-producing Escherichia coli (VTEC) O157 by beef cows in Scotland, where there is a particularly high rate of human infection. Thirty-two herds were visited at least monthly over approximately 1 year for collection of fresh faecal pat samples and information on management factors. The faecal pat samples were tested for VTEC O157 by established culture and immunomagnetic separation methods. Questionnaires were completed at the monthly visits to record management factors. Data were analysed using both univariate and multi-factor (GLMM) analysis. Changes in the number of cows in a group, dogs, wild geese, housing, and the feeding of draff (distillers' grains) were statistically significant as risk factors. The event of calving appeared to reduce the likelihood of shedding. Any effects of weaning or turnout were not statistically significant. It appears that the rate of shedding of VTEC O157 is influenced by several factors but possibly the most important of these are the circumstances of animals being housed, or, when outside, the presence of wild geese.


Comparison of subcellular partitioning, distribution, and internal speciation of Cu between Cu-tolerant and naïve populations of Dendrodrilus rubidus Savigny.
When considering contaminated site ecology and ecological risk assessment a key question is whether organisms that appear unaffected by accumulation of contaminants are tolerant or resistant to those contaminants. A population of Dendrodrilus rubidus Savigny earthworms from the Coniston Copper Mines, an area of former Cu mining, exhibit increased tolerance and accumulation of Cu relative to a nearby non-Cu exposed population. Distribution of total Cu between different body parts (posterior, anterior, body wall) of the two populations was determined after a 14 day exposure to 250 mg Cu kg(-1) in Cu-amended soil. Cu concentrations were greater in Coniston earthworms but relative proportions of Cu in different body parts were the same between populations. Cu speciation was determined using extended X-ray absorption fine structure spectroscopy (EXAFS). Cu was coordinated to O atoms in the exposure soil but to S atoms in the earthworms. There was no difference in this speciation between the different earthworm populations. In another experiment earthworms were exposed to a range of Cu concentrations (200-700 mg Cu kg(-1)). Subcellular partitioning of accumulated Cu was determined. Coniston earthworms accumulated more Cu but relative proportions of Cu in the different fractions (cytosol > granular > tissue fragments, cell membranes, and intact cells) were the same between populations. Results suggest that Coniston D. rubidus are able to survive in the Cu-rich Coniston Copper Mines soil through enlargement of the same Cu storage reservoirs that exist in a nearby non-Cu exposed population.


Dynamics of Cochlear Nonlinearity.
Dynamic aspects of cochlear mechanical compression were studied by recording basilar membrane (BM) vibrations evoked by tone pairs ("beat stimuli") in the 11-19 kHz region of the gerbil cochlea. The frequencies of the stimulus components were varied to produce a range of "beat rates" at or near the characteristic frequency (CF) of the BM site under study, and the amplitudes of the components were balanced to produce near perfect periodic cancellations, visible as sharp notches in the envelope of the BM response. We found a compressive relation between instantaneous stimulus intensity and BM response magnitude that was strongest at low beat rates (e.g., 10-100 Hz). At higher beat rates, the amount of compression reduced progressively (i.e. the responses became linearized), and the rising and falling flanks of the response envelope showed increasing amounts of hysteresis; the rising flank becoming steeper than the falling flank. This hysteresis indicates that cochlear mechanical compression is not instantaneous, and is suggestive of a gain control mechanism having finite attack and release times. In gain control terms, the linearization that occurs at higher beat rates occurs because the instantaneous gain becomes smoothened, or low-pass filtered, with respect to the magnitude fluctuations in the stimulus. In terms of peripheral processing, the linearization corresponds to an enhanced coding, or decompression, of rapid amplitude modulations. These findings are relevant both to those who wish to understand the underlying mechanisms and those who need a realistic model of nonlinear processing by the auditory periphery.


Surgeon's Neck Posture during Spine Surgeries: "The Unrecognised Potential Occupational Hazard".
Observational study. The purpose of this study is to analyze the surgeon's neck postures while performing lumbar spinal surgeries. Lumbar spinal surgeries are on rising trend, and with increase in number of procedures, the average time spent by a spine surgeon performing surgical procedures is also increasing. The effect of operating posture on the surgeon's neck is largely unknown. From the studies conducted on usage of smartphones, abnormal neck postures, especially the forward head posture (FHP), were found to adversely affect the cervical spine of individuals. The present study analyzes the neck position of spine surgeons during lumbar spine surgeries. Sixty video recordings (25 open transforaminal lumbar interbody fusions [TLIFs] and 35 lumbar decompression [LD] procedures - 15 with headlight and 20 with operating microscope) of surgeries performed by three spine surgeons of different heights were analyzed. Running videos of the surgeries were recorded concentrating on the surgeons with reflective markers taped to their surface landmarks corresponding to C7 spinous process, tragus of the ear, and outer canthus of the eye. Video recordings were standardized by a fixed video recorder in the same operating theater. Snapshots from the video were obtained whenever the surgeon changes the position. Head flexion angle (HFA), neck flexion angle (NFA), and cervical angle (CA) were measured and analyzed. During TLIF, HFA and NFA were significantly higher during the phases of decompression and fusion (P < 0.05). The average CA of all surgeons was lower, thereby adversely affecting the cervical spine (20.15° ± 5.05°). During LD, CA showed significant difference between usage of microscope and headlight (P < 0.001). Surgeon's FHP is frequently caused by a compromise between the need to perform surgery with hands, without elevating the arms, and simultaneous control of gaze at surgical field. The usage of microscope was found to reduce the stress on neck while performing surgery.


G protein-coupled receptor Gpr4 senses amino acids and activates the cAMP-PKA pathway in Cryptococcus neoformans.
The Galpha protein Gpa1 governs the cAMP-PKA signaling pathway and plays a central role in virulence and differentiation in the human fungal pathogen Cryptococcus neoformans, but the signals and receptors that trigger this pathway were unknown. We identified seven putative proteins that share identity with known G protein-coupled receptors (GPCRs). One protein, Gpr4, shares limited sequence identity with the Dictyostelium discoideum cAMP receptor cAR1 and the Aspergillus nidulans GPCR protein GprH and also shares structural similarity with the Saccharomyces cerevisiae receptor Gpr1. gpr4 mutants exhibited reduced capsule production and mating defects, similar to gpa1 mutants, and exogenous cAMP suppressed both gpr4 mutant phenotypes. Epistasis analysis provides further evidence that Gpr4 functions upstream of the Galpha subunit Gpa1. Gpr4-Gpr4 homomeric interactions were observed in the yeast two-hybrid assay, and Gpr4 was shown to physically interact with Gpa1 in the split-ubiquitin system. A Gpr4::DsRED fusion protein was localized to the plasma membrane and methionine was found to trigger receptor internalization. The analysis of intracellular cAMP levels showed that gpr4 mutants still respond to glucose but not to certain amino acids, such as methionine. Amino acids might serve as ligands for Gpr4 and could contribute to engage the cAMP-PKA pathway. Activation of the cAMP-PKA pathway by glucose and amino acids represents a nutrient coincidence detection system shared in other pathogenic fungi.


Ending open defecation in rural Tanzania: which factors facilitate latrine adoption?
Diarrheal diseases account for 7% of deaths in children under five years of age in Tanzania. Improving sanitation is an essential step towards reducing these deaths. This secondary analysis examined rural Tanzanian households' sanitation behaviors and attitudes in order to identify barriers and drivers to latrine adoption. The analysis was conducted using results from a cross-sectional study of 1000 households in five rural districts of Tanzania. Motivating factors, perceptions, and constraints surrounding open defecation and latrine adoption were assessed using behavioral change theory. Results showed a significant association between use of improved sanitation and satisfaction with current sanitation facility (OR: 5.91; CI: 2.95-11.85; p = 0.008). Livestock-keeping was strongly associated with practicing open defecation (OR: 0.22; CI 0.063-0.75; p < 0.001). Of the 93 total households that practiced open defecation, 79 (85%) were dissatisfied with the practice, 62 (67%) had plans to build a latrine and 17 (18%) had started saving for a latrine. Among households that planned to build a latrine, health was the primary reason stated (60%). The inability to pay for upgrading sanitation infrastructure was commonly reported among the households. Future efforts should consider methods to reduce costs and ease payments for households to upgrade sanitation infrastructure. Messages to increase demand for latrine adoption in rural Tanzania should integrate themes of privacy, safety, prestige and health. Findings indicate a need for lower cost sanitation options and financing strategies to increase household ability to adopt sanitation facilities.


Survival of community-dwelling older people: the effect of cognitive impairment and social engagement.
To examine the association and interaction between cognitive impairment and social support and mortality. Prospective cohort study. Fifty-three family practices in the United Kingdom. Community-dwelling people (aged > or =75) participating in the Medical Research Council Trial of the Assessment and Management of Older People in the Community (10,720 individual subjects analyzed). Cognition was measured using the Mini-Mental State Examination. Social engagement was assessed using categorical data on marital status, living situation, availability of assistance, availability of a confidant, and frequency of social contact. The primary outcome was all-cause mortality. The prevalence of cognitive impairment was 13.0% (mild) and 2.0% (moderate to severe). In Cox survival models (fully adjusted for physical health, lifestyle, daily function, and depression), there was a consistent association between greater cognitive impairment and mortality risk (mild cognitive impairment, hazard ratio (HR)=1.31, 95% confidence interval (CI)=1.21-1.40; moderate to severe cognitive impairment, HR=1.64, 95% CI=1.41-1.93. Mortality risk was greater in the medium (HR=1.09, 95% CI=1.02-1.16) and low social engagement groups (HR=1.17, 95% CI=1.05-1.29) than in those with the highest level of social engagement. Lower social engagement did not increase mortality risk in those who were more cognitively impaired. Cognitive impairment and social support are independent risk factors for mortality. Interventions that promote early identification and management of cognitive impairment and enhance social support for older people may decrease mortality and produce public health benefits.


Dose tapering and discontinuation of biological therapy in rheumatoid arthritis patients in routine care - 2-year outcomes and predictors.
A cohort of routine care RA patients in sustained remission had biological DMARD (bDMARDs) tapered according to a treatment guideline. We studied: the proportion of patients whose bDMARD could be successfully tapered or discontinued; unwanted consequences of tapering/discontinuation; and potential baseline predictors of successful tapering and discontinuation. One-hundred-and-forty-three patients (91% receiving TNF inhibitor and 9% a non-TNF inhibitor) with sustained disease activity score (DAS28-CRP)⩽2.6 and no radiographic progression the previous year were included. bDMARD was reduced to two-thirds of standard dose at baseline, half after 16 weeks, and discontinued after 32 weeks. Patients who flared (defined as either DAS28-CRP ⩾ 2.6 and ΔDAS28-CRP ⩾ 1.2 from baseline, or erosive progression on X-ray and/or MRI) stopped tapering and were escalated to the previous dose level. One-hundred-and-forty-one patients completed 2-year follow-up. At 2 years, 87 patients (62%) had successfully tapered bDMARDs, with 26 (18%) receiving two-thirds of standard dose, 39 (28%) half dose and 22 (16%) having discontinued; and 54 patients (38%) were receiving full dose. ΔDAS28-CRP0-2yrs was 0.1((-0.2)-0.4) (median (interquartile range)) and mean ΔTotal-Sharp-Score0-2yrs was 0.01(1.15)(mean(s.d.)). Radiographic progression was observed in nine patients (7%). Successful tapering was independently predicted by: ⩽1 previous bDMARD, male gender, low baseline MRI combined inflammation score or combined damage score. Negative IgM-RF predicted successful discontinuation. By implementing a clinical guideline, 62% of RA patients in sustained remission in routine care were successfully tapered, including 16% successfully discontinued at 2 years. Radiographic progression was rare. Maximum one bDMARDs, male gender, and low baseline MRI combined inflammation and combined damage scores were independent predictors for successful tapering.


Beyond structure: ultrafast X-ray absorption spectroscopy as a probe of non-adiabatic wavepacket dynamics.
The excited state non-adiabatic dynamics of polyatomic molecules, leading to the coupling of structural and electronic dynamics, is a fundamentally important yet challenging problem for both experiment and theory. Ongoing developments in ultrafast extreme vacuum ultraviolet (XUV) and soft X-ray sources present new probes of coupled electronic-structural dynamics because of their novel and desirable characteristics. As one example, inner-shell spectroscopy offers localized, atom-specific probes of evolving electronic structure and bonding (via chemical shifts). In this work, we present the first on-the-fly ultrafast X-ray time-resolved absorption spectrum simulations of excited state wavepacket dynamics: photo-excited ethylene. This was achieved by coupling the ab initio multiple spawning (AIMS) method, employing on-the-fly dynamics simulations, with high-level algebraic diagrammatic construction (ADC) X-ray absorption cross-section calculations. Using the excited state dynamics of ethylene as a test case, we assessed the ability of X-ray absorption spectroscopy to project out the electronic character of complex wavepacket dynamics, and evaluated the sensitivity of the calculated spectra to large amplitude nuclear motion. In particular, we demonstrate the pronounced sensitivity of the pre-edge region of the X-ray absorption spectrum to the electronic and structural evolution of the excited-state wavepacket. We conclude that ultrafast time-resolved X-ray absorption spectroscopy may become a powerful tool in the interrogation of excited state non-adiabatic molecular dynamics.


Dietary Interventions for the Prevention of Type 2 Diabetes in High-Risk Groups: Current State of Evidence and Future Research Needs.
A series of large-scale randomised controlled trials have demonstrated the effectiveness of lifestyle change in preventing type 2 diabetes in people with impaired glucose tolerance. Participants in these trials consumed a low-fat diet, lost a moderate amount of weight and/or increased their physical activity. Weight loss appears to be the primary driver of type 2 diabetes risk reduction, with individual dietary components playing a minor role. The effect of weight loss via other dietary approaches, such as low-carbohydrate diets, a Mediterranean dietary pattern, intermittent fasting or very-low-energy diets, on the incidence of type 2 diabetes has not been tested. These diets-as described here-could be equally, if not more effective in preventing type 2 diabetes than the tested low-fat diet, and if so, would increase choice for patients. There is also a need to understand the effect of foods and diets on beta-cell function, as the available evidence suggests moderate weight loss, as achieved in the diabetes prevention trials, improves insulin sensitivity but not beta-cell function. Finally, prediabetes is an umbrella term for different prediabetic states, each with distinct underlying pathophysiology. The limited data available question whether moderate weight loss is effective at preventing type 2 diabetes in each of the prediabetes subtypes.


Different accuracies of rapid enzyme-linked immunosorbent, turbidimetric, and agglutination D-dimer assays for thrombosis exclusion: impact on diagnostic work-ups of outpatients with suspected deep vein thrombosis and pulmonary embolism.
The requirement for a safe diagnostic strategy should be based on an overall posttest incidence of venous thromboembolism (VTE) of less than 1%, with a negative predictive value of more than 99 to 100% during 3-month follow-up. Compression ultrasonography (CUS) and spiral computed tomography (CT) currently are the methods of choice to confirm or rule out deep venous thrombosis (DVT) and pulmonary embolism (PE), respectively. CUS has a negative predictive value (NPV) of 97 to 98%, indicating the need to improve the diagnostic work-up of patients with suspected DVT by clinical score assessment and D-dimer testing. Spiral CT as a stand-alone method detects all clinically relevant PEs and a large number of alternative diagnoses. It rules out PE with a NPV of 98 to 99%. Spiral CT is expensive, emphasizing the need to improve the diagnostic work-up of patients with suspected PE by the use of clinical score assessment and D-dimer testing. Clinical score assessment for DVT and PE has not safely ruled out VTE in multicenter studies and in routine daily practices. Modification of the Wells clinical score assessment for DVT by elimination of the "minus 2 points" for alternative diagnosis will improve the reproducibility of the clinical score assessment. The combination of a first negative CUS and a negative SimpliRed or an enzyme-linked immunosorbent assay (ELISA) VIDAS D-dimer of < 1,000 ng/mL safely exclude DVT (NPV > 99%) irrespective of clinical score assessment and without the need to repeat CUS in approximately 60 to 70% of patients. The rapid quantitative and qualitative agglutination D-dimer assays for the exclusion of VTE are not sensitive enough as stand-alone tests and should be used in combination with clinical score assessment. A normal rapid ELISA VIDAS D-dimer test as a stand-alone test safely excludes DVT and PE, with a NPV of 99 to 100%, irrespective of clinical score, without the need of CUS or spiral CT. The combined strategy of a rapid ELISA VIDAS D-dimer followed by objective testing with CUS for DVT and by spiral CT for PE will reduce the need for noninvasive imaging techniques by 40 to 50%.


Emotionally abusive behavior in young couples: exploring a role for implicit aggression.
Emotionally abusive behaviors reported across a 6-month period in intimate relationships were examined. There were 269 participants aged 18-25 years who took part (98 men, 171 women). All completed the Multidimensional Measure of Emotional Abuse (MMEA) and a measure of implicit aggression, the Puzzle Test. Implicit processing refers to subtle cognitive processing that occurs outside of conscious awareness. This study focused on aggressive implicit processing. Overall emotional victimization by a partner was associated with increased implicit aggressive levels, particularly for women. Those classified as perpetrators/victims (mutual aggressors and victims) were also predicted by increased implicit aggression. Women reported higher levels of implicit aggression than men. Results are discussed regarding future research and the value of theory in understanding the association between emotional abuse and implicit aggression.


A large focus of naturally acquired Plasmodium knowlesi infections in human beings.
About a fifth of malaria cases in 1999 for the Kapit division of Malaysian Borneo had routinely been identified by microscopy as Plasmodium malariae, although these infections appeared atypical and a nested PCR assay failed to identify P malariae DNA. We aimed to investigate whether such infections could be attributable to a variant form of P malariae or a newly emergent Plasmodium species. We took blood samples from 208 people with malaria in the Kapit division between March, 2000, and November, 2002. The small subunit ribosomal RNA and the circumsporozoite protein genes were sequenced for eight isolates that had been microscopically identified as P malariae. All blood samples were characterised with a genus-specific and species-specific nested PCR assay together with newly designed P knowlesi-specific primers. All DNA sequences were phylogenetically indistinguishable from those of P knowlesi, a malaria parasite of long-tailed macaque monkeys, but were significantly different from other malaria parasite species. By PCR assay, 120 (58%) of 208 people with malaria tested positive for P knowlesi, whereas none was positive for P malariae. P knowlesi parasites in human erythrocytes were difficult to distinguish from P malariae by microscopy. Most of the P knowlesi infections were in adults and we did not note any clustering of cases within communities. P knowlesi infections were successfully treated with chloroquine and primaquine. Naturally acquired P knowlesi infections, misdiagnosed by microscopy mainly as P malariae, accounted for over half of all malaria cases in our study. Morphological similarities between P knowlesi and P malariae necessitate the use of molecular methods for correct identification. Further work is needed to determine whether human P knowlesi infections in the Kapit division are acquired from macaque monkeys or whether a host switch to human beings has occurred.


Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma.
Ectopic lymphoid-like structures (ELSs) are often observed in cancer, yet their function is obscure. Although ELSs signify good prognosis in certain malignancies, we found that hepatic ELSs indicated poor prognosis for hepatocellular carcinoma (HCC). We studied an HCC mouse model that displayed abundant ELSs and found that they constituted immunopathological microniches wherein malignant hepatocyte progenitor cells appeared and thrived in a complex cellular and cytokine milieu until gaining self-sufficiency. The egress of progenitor cells and tumor formation were associated with the autocrine production of cytokines previously provided by the niche. ELSs developed via cooperation between the innate immune system and adaptive immune system, an event facilitated by activation of the transcription factor NF-κB and abolished by depletion of T cells. Such aberrant immunological foci might represent new targets for cancer therapy.


Semi-continuous in situ magnetic separation for enhanced extracellular protease production-modeling and experimental validation.
In modern biotechnology proteases play a major role as detergent ingredients. Especially the production of extracellular protease by Bacillus species facilitates downstream processing because the protease can be directly harvested from the biosuspension. In situ magnetic separation (ISMS) constitutes an excellent adsorptive method for efficient extracellular protease removal during cultivation. In this work, the impact of semi-continuous ISMS on the overall protease yield has been investigated. Results reveal significant removal of the protease from Bacillus licheniformis cultivations. Bacitracin-functionalized magnetic particles were successfully applied, regenerated and reused up to 30 times. Immediate reproduction of the protease after ISMS proved the biocompatibility of this integrated approach. Six subsequent ISMS steps significantly increased the overall protease yield up to 98% because proteolytic degradation and potential inhibition of the protease in the medium could be minimized. Furthermore, integration of semi-continuous ISMS increased the overall process efficiency due to reduction of the medium consumption. Process simulation revealed a deeper insight into protease production, and was used to optimize ISMS steps to obtain the maximum overall protease yield.


Cost analysis of osteoradionecrosis.
Osteoradionecrosis is a significant complication of head and neck cancer treatment, and its most severe form (grade III) necessitates radical surgery. This study aimed to compare the cost of free-flap reconstructive surgery for grade III osteoradionecrosis and similar non-osteoradionecrosis cases in order to assess the cost burden of osteoradionecrosis treatment. All patients who underwent free-flap reconstructive surgery for osteoradionecrosis between July 2004 and July 2010 at Auckland City Hospital (19 patients) were identified, and relevant data were collected retrospectively. These patients were matched in terms of age and sex with patients who underwent free-flap reconstructive surgery. The treatment cost was 44 per cent higher in osteoradionecrosis patients when compared to non-osteoradionecrosis patients. The significant financial burden on the health system, and the growing evidence for the effectiveness of pentoxifylline, tocopherol and clodronate, should prompt us to explore this alternative treatment further.


Rapamycin inhibits platelet-derived growth factor-induced collagen, but not fibronectin, synthesis in rat mesangial cells.
Rapamycin, a macrocyclic lactone, is effective in reducing the incidence of acute rejection after renal transplantation. The inhibitory effects of rapamycin on lymphocyte proliferation and the molecular mechanisms that were involved have been described. However, its effects on glomerular mesangial cells have not been clearly understood, and here, we examined the effect of rapamycin on platelet-derived growth factor (PDGF)-induced extracellular matrix synthesis as well as cell proliferation in mesangial cells. Rat mesangial cells were isolated from the glomeruli of Sprague-Dawley rats and cultured with Dulbecco's modified Eagles medium containing 20% fetal bovine serum. Different concentrations of rapamycin were administered 1 hour before the addition of 10 ng/ml of PDGF into growth arrested and synchronized cells. Cell proliferation was assessed by [3H]thymidine incorporation, total collagen synthesis by [3H]proline incorporation, and fibronectin secretion into the medium by Western blot analysis. In the mesangial cells, PDGF increased cell proliferation by 4.6-fold, total collagen synthesis by 1.8-fold, and fibronectin secretion by 3.2-fold. Rapamycin above 10 nM significantly inhibited PDGF-induced proliferation and collagen synthesis, but the treatment of rapamycin up to 1 microM did not show any significant effects on PDGF-induced fibronectin secretion. These inhibitory effects of rapamycin on PDGF-induced mesangial cell proliferation and collagen synthesis reflect the potential value of rapamycin in the prevention and treatment of glomerulosclerosis in patients with chronic allograft nephropathy.


A yeast glycoprotein shows high-affinity binding to the broadly neutralizing human immunodeficiency virus antibody 2G12 and inhibits gp120 interactions with 2G12 and DC-SIGN.
The human immunodeficiency virus type 1 (HIV-1) envelope (Env) protein contains numerous N-linked carbohydrates that shield conserved peptide epitopes and promote trans infection by dendritic cells via binding to cell surface lectins. The potent and broadly neutralizing monoclonal antibody 2G12 binds a cluster of high-mannose-type oligosaccharides on the gp120 subunit of Env, revealing a conserved and highly exposed epitope on the glycan shield. To find an effective antigen for eliciting 2G12-like antibodies, we searched for endogenous yeast proteins that could bind to 2G12 in a panel of Saccharomyces cerevisiae glycosylation knockouts and discovered one protein that bound weakly in a Delta pmr1 strain deficient in hyperglycosylation. 2G12 binding to this protein, identified as Pst1, was enhanced by adding the Delta mnn1 deletion to the Delta pmr1 background, ensuring the exposure of terminal alpha1,2-linked mannose residues on the D1 and D3 arms of high-mannose glycans. However, optimum 2G12 antigenicity was found when Pst1, a heavily N-glycosylated protein, was expressed with homogenous Man(8)GlcNAc(2) structures in Delta och1 Delta mnn1 Delta mnn4 yeast. Surface plasmon resonance analysis of this form of Pst1 showed high affinity for 2G12, which translated into Pst1 efficiently inhibiting gp120 interactions with 2G12 and DC-SIGN and blocking 2G12-mediated neutralization of HIV-1 pseudoviruses. The high affinity of the yeast glycoprotein Pst1 for 2G12 highlights its potential as a novel antigen to induce 2G12-like antibodies.


Hepatic expression of mature transforming growth factor beta 1 in transgenic mice results in multiple tissue lesions.
Aberrant expression of transforming growth factor beta 1 (TGF-beta 1) has been implicated in a number of disease processes, particularly those involving fibrotic and inflammatory lesions. To determine the in vivo effects of overexpression of TGF-beta 1 on the function and structure of hepatic as well as extrahepatic tissues, transgenic mice were generated containing a fusion gene (Alb/TGF-beta 1) consisting of modified porcine TGF-beta 1 cDNA under the control of the regulatory elements of the mouse albumin gene. Five transgenic lines were developed, all of which expressed the Alb/TGF-beta 1 transgene selectively in hepatocytes. The transgenic line 25 expressing the highest level of the transgene in the liver also had high (> 10-fold over control) plasma levels of TGF-beta 1. Hepatic fibrosis and apoptotic death of hepatocytes developed in all the transgenic lines but was more pronounced in line 25. The fibrotic process was characterized by deposition of collagen around individual hepatocytes and within the space of Disse in a radiating linear pattern. Several extrahepatic lesions developed in line 25, including glomerulonephritis and renal failure, arteritis and myocarditis, as well as atrophic changes in pancreas and testis. The results from this transgenic model strongly support the proposed etiological role for TGF-beta 1 in a variety of fibrotic and inflammatory disorders. The transgenic model may also provide an appropriate paradigm for testing therapeutic interventions aimed at neutralizing the detrimental effects of this important cytokine.


Effect of organic and inorganic selenium supplementation on semen quality and blood enzymes in buffalo bulls.
The present study aimed to evaluate the effect of organic and inorganic selenium (Se) supplementation on semen quality and blood serum profiles of buffalo bulls. Nine mature buffalo bulls were divided into three groups: control (non-supplemented); organic Se (10 mg Sel-Plex®/head twice weekly) and inorganic Se (10 mg sodium selenite/head twice weekly). Semen was collected twice a week for 3 months during Se supplementation. Semen properties were evaluated from fresh ejaculate. Moreover, fructose concentration, aspartate and alanine transaminase (AST and ALT) activities, total protein and total cholesterol were assayed in seminal plasma. Additionally AST, ALT, testosterone and Se levels were determined in the blood serum. Results showed that Se supplementation significantly (P < 0.05) influences the semen parameters during 3 months of treatment. Organic Se significantly (P < 0.05) increased the percentage of viable sperms compared to inorganic Se and the control group. Fructose concentration was significantly higher (P < 0.05) in the seminal plasma of organic Se-treated bulls. Serum testosterone and Se concentrations were significantly (P < 0.05) increased in the Se supplemented groups than the control group. In conclusion, Se supplementation improved the parameters of buffalo bull semen and more precisely, organic Se was more effective for the improvement of semen quality and some blood components than inorganic Se.


Influence of statistician involvement on reporting of randomized clinical trials in medical oncology.
Ideally, statisticians should be involved in the design, analysis, and reporting of randomized clinical trials (RCTs). This study assessed the impact of a statistician involvement in published medical oncology RCTs between 2005 and 2009. The reporting quality of each publication was rated using the Overall Reporting Quality Score on the basis of either 2001 or 2010 Consolidated Standards of Reporting Trials criteria. A four-question email survey on the statistical design and analysis was sent to the corresponding authors of each trial. Nonresponders were approached a maximum of three times. Overall, 107 responses were received from 357 solicited authors (30%). Corresponding authors from industry-funded RCTs were less likely to respond (51 vs. 65%, P=0.013). The same person was responsible for statistical design and analyses in 47% of cases. Overall, the statistician involved held a PhD (or equivalent) in statistics in most cases. The statisticians responsible for the statistical design and analysis were listed as coauthors in 68 and 81% of RCT manuscripts. There was no statistically significant impact on manuscript reporting quality of the degree of statistician involvement in manuscript preparation. Fewer trials were reported as positive when the responsible statistician was listed as a coauthor. It is possible that RCTs included in this review are in general of higher quality or were more likely to have a greater level of statistician involvement than smaller, single-arm, or unpublished studies. This imbalance could explain the lack of significant difference observed in the Overall Reporting Quality Score between trials where statisticians were listed as coauthors or not.


Quality of life and patient satisfaction after one-stage implant-based breast reconstruction with an acellular dermal matrix versus two-stage breast reconstruction (BRIOS): primary outcome of a randomised, controlled trial.
There is increasing interest in the use of acellular dermal matrices (ADMs) in implant-based breast reconstruction (IBBR). Suggested advantages are that ADMs facilitate one-stage IBBR and improve aesthetic outcomes. We compared immediate one-stage ADM-assisted IBBR with two-stage IBBR (current standard of care). Our previously reported secondary endpoint showed that one-stage ADM-assisted IBBR was associated with significantly more adverse outcomes. Here, we present the primary endpoint results aiming to assess whether one-stage IBBR with ADM provides higher patient-reported quality of life (QOL) compared with two-stage IBBR. This multicentre, open-label, randomised controlled trial (BRIOS study) was done in eight hospitals in the Netherlands. We recruited women aged older than 18 years with breast carcinoma or a genetic predisposition who intended to undergo skin-sparing mastectomy and immediate IBBR. Participants were randomly assigned to undergo one-stage IBBR with ADM (Strattice, LifeCell, Branchburg, NJ, USA) or two-stage IBBR. Randomisation was stratified by centre and indication for surgery (oncological or prophylactic) in blocks of ten participants. The primary endpoint was patient-reported QOL, as measured with the BREAST-Q (ie, health-related QOL scales and satisfaction scales), in the modified intention-to-treat population. The study follow-up is complete. This study is registered with the Netherlands Trial Register, number NTR5446. Between April 14, 2013, and May 29, 2015, we enrolled 142 women, of whom 69 were randomly assigned to receive one-stage ADM-assisted IBBR and 73 to receive two-stage IBBR. After exclusions, the modified intention-to-treat population comprised 60 patients in the one-stage group and 61 patients in the two-stage group. Of these, 48 women (mean follow-up 17·0 months [SD 7·8]) in the one-stage group and 44 women (17·2 months [SD 6·7]) in the two-stage group completed the BREAST-Q at least 1 year after implant placement. We found no significant differences in postoperative patient-reported QOL domains, including physical wellbeing (one-stage mean 78·0 [SD 14·1] vs two-stage 79·3 [12·2], p=0·60), psychosocial wellbeing (72·6 [17·3] vs 72·8 [19·6], p=0·95), and sexual wellbeing (58·0 [17·0] vs 57·1 [19·5], p=0·82), or in the patient-reported satisfaction domains: satisfaction with breasts (63·4 [15·8] vs 60·3 [15·4], p=0·35) and satisfaction with outcome (72·8 [19·1] vs 67·8 [16·3], p=0·19). Taken together with our previously published findings, one-stage IBBR with ADM does not yield superior results in terms of patient-reported QOL compared with two-stage IBBR. Risks for adverse outcomes were significantly higher in the one-stage ADM group. Use of ADM for one-stage IBBM should be considered on a case-by-case basis. Pink Ribbon, Nuts-Ohra, and LifeCell.


[The international normalization ratio in the monitoring of oral anticoagulant therapy].
Oral anticoagulants are employed very frequently in the prophylaxis and treatment of several diseases. For their optimal effectiveness, many vigilance schedules have been proposed but none has proved to be 100% effective. The international normalization ratio (INR) can be a safer way to monitor oral anticoagulation, and our objective was to determine its clinical usefulness. A prothrombin time test (PT) was carried out by means of either a chromogenic or a coagulometric method, and an INR was obtained using the ratio of the PT patient/PT control elevated to an exponential given by the international sensitivity index (ISI) of our thromboplastin. Our objective was to maintain our patients in a therapeutical INR range between two and three. We present our experience with 77 patients and 810 results during an 18 months period. We observed 26 cases of hemorrhage and three of thrombosis. In all these cases, the INR was out of the desired therapeutical range. No deaths occurred in our patients. Our analysis showed a significative disagreement between the INR and the prothrombin time ratio (PTR) but a better correlation with hemorrhage and thrombosis was seen with the INR than with the PTR. Our experience supports the use of INR in the clinical vigilance of oral anticoagulation as a useful method.


Promising ethical arguments for product differentiation in the organic food sector. A mixed methods research approach.
Ethical consumerism is a growing trend worldwide. Ethical consumers' expectations are increasing and neither the Fairtrade nor the organic farming concept covers all the ethical concerns of consumers. Against this background the aim of this research is to elicit consumers' preferences regarding organic food with additional ethical attributes and their relevance at the market place. A mixed methods research approach was applied by combining an Information Display Matrix, Focus Group Discussions and Choice Experiments in five European countries. According to the results of the Information Display Matrix, 'higher animal welfare', 'local production' and 'fair producer prices' were preferred in all countries. These three attributes were discussed with Focus Groups in depth, using rather emotive ways of labelling. While the ranking of the attributes was the same, the emotive way of communicating these attributes was, for the most part, disliked by participants. The same attributes were then used in Choice Experiments, but with completely revised communication arguments. According to the results of the Focus Groups, the arguments were presented in a factual manner, using short and concise statements. In this research step, consumers in all countries except Austria gave priority to 'local production'. 'Higher animal welfare' and 'fair producer prices' turned out to be relevant for buying decisions only in Germany and Switzerland. According to our results, there is substantial potential for product differentiation in the organic sector through making use of production standards that exceed existing minimum regulations. The combination of different research methods in a mixed methods approach proved to be very helpful. The results of earlier research steps provided the basis from which to learn - findings could be applied in subsequent steps, and used to adjust and deepen the research design.


Spinal adrenergic mechanisms regulating sympathetic outflow to blood vessels.
The role of descending spinal catecholamine (CA)-containing fibers in cardiovascular regulation was examined. Monoamine-containing fibers were visualized by fluorescence histochemical methods at the cervical, thoracic, and lumbar spinal segments. Two major groups of descending CA-containing axons were located in the lateral funiculus at the midcervical spinal level. At the thoracolumbar spinal segments CA-containing terminals were concentrated mostly around cells of the intermediolateral nucleus. In addition a distinct CA-containing fasciculus was observed at the level of the sympathetic nucleus which appeared to course toward the opposite site of the cord. To evaluate the role of the efferent CA-containing fibers, changes in heart rate, arterial pressure, femoral blood flow, and calculated peak vascular resistance were elicited by electrical stimulation of selected sites in the midcervical spinal cord. Although changes in femoral flow and arterial pressure were evoked from many midcervical sites, there was a distinct correlation between the magnitude of peak femoral resistance elevation and density of CA-containing axons activated. Furthermore, efferent spinal vasoconstrictor outflow to the hindlimbs crosses below the cervical level. This observation is in good agreement with fluorescence microscopy studies revealing CA-containing fibers which appear to decussate. Pharmacological studies also were undertaken to evaluate transmission in spinal vasopressor pathways. In these studies alpha-adrenergic receptor antagonists and agonists were perfused into the spinal subarachnoid space. Heart rate, arterial pressure, femoral flow, and femoral resistance responses elicited from efferent spinal pathways were significantly attenuated following superfusion of the spinal cord with the alpha-antagonists BE-2254 (HEAT) and phentolamine. It was shown that inhibition of the centrally evoked responses was due to actions of the alpha-antagonists at a spinal locus and not due to peripheral vascular alpha-receptor blockade. Spinal perfusion with the alpha-receptor agonist norepinephrine potentiated cardiovascular responses. Likewise, loading with the norepinephrine precursor 3,4-dihydroxy-L-phenylalanine (L-dopa) enhanced vasoconstrictor responses evoked in the cross-perfused hindlimb of p-chlorophenylalanine-pretreated cats. These observations support the idea that bulbospinal CA-containing fibers relay excitatory impulses to preganglionic vasoconstrictor neurons and that spinal alpha-adrenergic receptor activation is necessary for transmission of this information.


Maximizing genetic representation in seed collections from populations of self and cross-pollinated banana wild relatives.
Conservation of plant genetic resources, including the wild relatives of crops, plays an important and well recognised role in addressing some of the key challenges faced by humanity and the planet including ending hunger and biodiversity loss. However, the genetic diversity and representativeness of ex situ collections, especially that contained in seed collections, is often unknown. This limits meaningful assessments against conservation targets, impairs targeting of future collecting and limits their use. We assessed genetic representation of seed collections compared to source populations for three wild relatives of bananas and plantains. Focal species and sampling regions were M. acuminata subsp. banksii (Papua New Guinea), M. balbisiana (Viet Nam) and M. maclayi s.l. (Bougainville, Papua New Guinea). We sequenced 445 samples using suites of 16-20 existing and newly developed taxon-specific polymorphic microsatellite markers. Samples of each species were from five populations in a region; 15 leaf samples from different individuals and 16 seed samples from one infructescence ('bunch') were analysed for each population. Allelic richness of seeds compared to populations was 51, 81 and 93% (M. acuminata, M. balbisiana and M. maclayi respectively). Seed samples represented all common alleles in populations but omitted some rarer alleles. The number of collections required to achieve the 70% target of the Global Strategy for Plant Conservation was species dependent, relating to mating systems. Musa acuminata populations had low heterozygosity and diversity, indicating self-fertilization; many bunches were needed (> 15) to represent regional alleles to 70%; over 90% of the alleles from a bunch are included in only two seeds. Musa maclayi was characteristically cross-fertilizing; only three bunches were needed to represent regional alleles; within a bunch, 16 seeds represent alleles. Musa balbisiana, considered cross-fertilized, had low genetic diversity; seeds of four bunches are needed to represent regional alleles; only two seeds represent alleles in a bunch. We demonstrate empirical measurement of representation of genetic material in seeds collections in ex situ conservation towards conservation targets. Species mating systems profoundly affected genetic representation in seed collections and therefore should be a primary consideration to maximize genetic representation. Results are applicable to sampling strategies for other wild species.


Long-Term Survivors of Pancreatic Cancer: A California Population-Based Study.
Pancreatic cancer continues to carry a poor prognosis with survival rates that have had minimal improvement over the past 4 decades. We report a population-based, comprehensive analysis of long-term survivors of pancreatic adenocarcinoma diagnosed in the diverse population of California. Data from the California Cancer Registry were used to evaluate long-term survival. A total of 70,442 patients diagnosed with pancreatic adenocarcinoma between 1988 and 2009 were identified. Logistic regression was used to identify factors associated with achieving 5-year survival. The overall 5-year survival was 2.5%, with minimal incremental improvements throughout the 3 decades. Age, stage, degree of differentiation, and surgical resection were associated with 5-year survival. Furthermore, younger age and receiving care at a National Cancer Institute-designated cancer center were similarly correlated with 5-year survival regardless of surgical intervention. In addition, we identified stage, differentiation, and adjuvant chemotherapy as significant factors for long-term survival in surgically resected patients. In the unresectable patients, Asian/Pacific islanders and Hispanics were significantly more likely to reach the 5-year milestone than non-Hispanic whites. Although pancreatic cancer mortality remains high, our study highlights baseline characteristics, treatment, biological factors, and ethnicity that are associated with long-term survival. These findings may serve as a springboard for further investigation.


Role of the R349 Gene and Its Repeats in the MIMIVIRE Defense System.
MIMIVIRE is a defense system described in lineage A Mimivirus (Mimiviridae family) that mediates resistance against Zamilon virophage. It is composed of putative helicase and nuclease associated with a gene of unknown function called R349, which contains four 15 bp repeats homologous to the virophage sequence. In a previous study, the silencing of such genes restored virophage susceptibility. Moreover, the CRISPR Cas-4 like activity of the nuclease has recently been characterized. In this study, a recently isolated Mimivirus of lineage A with R349 gene lacking 3 of 4 repeats was demonstrated to be susceptible to Zamilon. To reinforce the importance of the R349 gene in the MIMIVIRE system, we developed and presented, for the first time to our knowledge, a protocol for Mimivirus genomic editing. By knocking out R349 gene in a Mimivirus lineage A, we observed the replication of Zamilon, indicating that this gene is critical in the resistance against this specific group of virophages.


Visible light photoinitiation of mesenchymal stem cell-laden bioresponsive hydrogels.
Biological activity can be added to synthetic scaffolds by incorporating functional peptide sequences that provide enzyme-mediated degradation sites, facilitate cellular adhesion or stimulate signaling pathways. Poly(ethylene glycol) diacrylate is a popular synthetic base for tissue engineering scaffolds because it creates a hydrophilic environment that can be chemically manipulated to add this biological functionality. Furthermore, the acrylate groups allow for encapsulation of cells using photopolymerization under physiological conditions. One complication with the addition of these peptides is that aromatic amino acids absorb light at 285 nm and compete with the ultraviolet (UV)-sensitive photoinitiators such as IrgacureTM 2959 (I2959), the most commonly used initiator for cytocompatible photoencapsulation of cells into synthetic scaffolds. In this study we define non-toxic conditions for photoencapsulation of human mesenchymal stem cells (hMSC) in PEGDA scaffolds using a visible light photoinitiator system composed of eosin Y, triethanolamine and 1-vinyl-2-pyrrolidinone. This visible light photoinitiator produced hydrogel scaffolds with an increased viability of encapsulated hMSCs and a more tightly crosslinked network in one-third the time of UV polymerization with I2959.